The premise of this proposal is that innate immunity may be the only resource left in HIV-1 infected individuals progressing to AIDS to deal with opportunistic infections such as MDR or XDR Mycobacterium tuberculosis (MTB). Given the CD4+ T cell population and function breakdown in AIDS, and associated loss of adaptive immunity responses and pathogen control, we believe that we can nevertheless resort to autophagy as an innate immunity process to combat MTB in HIV-infected macrophages. In this project we will delineate the previously unappreciated but rapidly emerging links between innate immunity (specifically IL-1 and pattern recognition receptors) and autophagy as an antimicrobial effector mechanism. Autophagy has been shown by us and others to eliminate intracellular MTB. Currently, there are two standard ways of inducing autophagy: by starvation and by the immunosuppressant rapamycin. Here, we propose to delineate additional immunological methods of inducing autophagy, following up on our published work showing that innate immunity pattern recognition receptors (PRR), e.g. Toll-like receptors (TLR), control autophagy. Moreover, our preliminary studies show that IL-1 can induce autophagy. In this project, we will delineate pathways for innate immunity induction of antimicrobial autophagy to understand how these newly recognized processes work. These studies will provide a foundation for use of autophagy agonists in difficult cases such as drug resistant MTB in AIDS patients. Hypothesis: We hypothesize that innate immunity receptors and mediators, specifically pattern recognition receptors (PRR) and IL1- receptor and their downstream signaling pathways induce autophagy as an antimycobacterial mechanism. We furthermore hypothesize that agonists of innate immunity receptors will, through autophagy, eliminate M. tuberculosis in HIV-coinfected macrophages, even in the absence of CD4+ T cells. The specific aims are: 1. Determine how IL-1 induces autophagy as an antimycobacterial innate immunity effector. 2. Delineate how TLRs induce autophagy as an antimycobacterial defense. 3. Define factors of MTB elimination by PRR-induced autophagy in HIV infected macrophages.